A randomized, double-blinded, placebo-controlled trial will be conducted to evaluate vortioxetine, an antidepressant with established pro-cognitive properties, for the treatment of cognitive deficits which develop during or after an infection consistent with COVID-19, continue for 2+ months, and are not explained by an alternative diagnosis (i.e., post-COVID-19 condition). Participants (aged 18-64 years) will receive vortioxetine (10-20 mg) or placebo for 8 weeks. Participants 65+ years will receive vortioxetine (5-10 mg) or placebo for 8 weeks. Changes in cognitive functioning from baseline to endpoint (week 8) will be assessed via the Digit Symbol Substitution Test (DSST). Study visits may be conducted remotely (e.g. via Zoom, by telephone), and/or in-person.

A significant percentage of individuals who have recovered from acute COVID-19 infection present with unabating, non-specific, distressing, and functionally impairing symptoms (i.e., post-COVID-19 condition). Commonly reported symptoms include, but are not limited to, cognitive impairment (e.g., "brain fog"), fatigue, apathy, depression, anxiety, insomnia, anergia, and loss of appetite. Toward the aim of identifying a common nomenclature and case definition, the World Health Organization (WHO) has recently proposed the moniker 'post COVID-19 condition'. It is estimated that approximately 10-30% of persons infected with COVID-19 experience characteristic symptoms persisting for more than 12 weeks following documentation of positive COVID-19 diagnosis.

Consensus exists that the phenomenology of post-COVID-19 condition is subserved by disturbance in immune-inflammatory systems. Currently, no treatment is identified as safe and effective for post-COVID-19 condition. A candidate treatment for post-COVID-19 condition should be capable of improving measures of cognitive function (i.e., objective and subjective), motivation and energy, as well as reducing fatigue. The rationale for prioritizing cognition as a primary therapeutic target is based on a concatenation of study results reporting that cognitive complaints/deficits and fatigue are some of the most common and debilitating features of post-COVID-19 condition. Preliminary evidence suggests that some antidepressants (e.g., SSRIs) are capable of reducing respiratory complications secondary to COVID-19 via putative mechanisms including, but not limited to, sigma-1 agonism and acid sphingomyelinase.

Vortioxetine is established as pro-cognitive, as evidenced by significant improvement on both subjective and objective measures. Vortioxetine is also documented to improve anticipatory and consummatory measures of reward function/anhedonia, improve general functioning, and measures of motivation and energy. Moreover, vortioxetine is not associated with emotional blunting and has preliminary evidence of improving sleep behaviour and circadian rhythms. The candidacy of vortioxetine as an effective treatment for post-COVID-19 condition is also strengthened by evidence indicating that vortioxetine exerts modulatory effects on cellular and cytokine systems known to be activated in persons with post-COVID-19 condition. Herein, we hypothesize that vortioxetine will be more effective than placebo in the treatment of cognitive impairment in persons with post-COVID-19 condition.

Inclusion Criteria

• Age 18+
• Meets WHO-defined post-COVID-19 condition (WHO definition: 'Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others* and generally have an impact on everyday functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time.') To ensure the above criteria is met, participants will only be included in the study if they meet all eligibility criteria more than 12 weeks from the onset of their acute Covid-19 symptoms or positive PCR/antigen test.
• Documented history of SARS-CoV-2 infection (positive PCR/antigen test during acute illness OR clinical diagnosis by physician during or after the acute illness).
• Subjective cognitive complaints as detected by the Perceived Deficits Questionnaire (PDQ)-5.
• Ability to provide written informed consent.
• Resident of Canada.

Exclusion Criteria

• Current symptoms are fully explained by major depressive disorder or bipolar disorder.
• Pre-existing conditions that may cause cognitive impairment, or symptoms similar to those seen in post-COVID-19 condition (e.g., major neurocognitive disorder, schizophrenia, chronic fatigue syndrome [CFS]/ encephalitis meningitis [EM]), as assessed by Mini International Neuropsychiatric Interview (MINI) 7.0.2.
• Inability to follow study procedures.
• Known intolerance to vortioxetine and/or prior trial of vortioxetine with demonstrated inefficacy.
• If participants are currently taking other antidepressants, they will be asked to discontinue the antidepressant for 2-4 weeks in order to participate in the study.
• Patients on other antidepressants are allowed to participate only if the antidepressant is prescribed at subtherapeutic doses for a primary indication other than mood disorders. Participants will be made aware in the consent form that the combination of the two antidepressants would be considered investigational and that the safety/efficacy profiles are unknown.
• Current alcohol or substance use disorder.
• Inability to provide consent.
• Current alcohol and/or substance use disorder as confirmed by the M.I.N.I 7.0.2.
• Presence of comorbid psychiatric disorder that is a primary focus of clinical concern as confirmed by the M.I.N.I. 7.0.2.
• Medications approved and/or employed off-label for cognitive dysfunction (e.g., psychostimulants).
• Any medication for a general medical disorder that, in the opinion of the investigator, may affect cognitive function.
• Use of benzodiazepines within 12 hours of cognitive assessments.
• Consumption of alcohol within 8 hours of cognitive assessments.
• Physical, cognitive, or language impairments sufficient to adversely affect data derived from cognitive assessments.
• Diagnosed reading disability or dyslexia.
• Clinically significant learning disorder by history.
• Electroconvulsive therapy (ECT) in the last 6 months.
• History of moderate or severe head trauma (e.g., loss of consciousness for >1 hour), other neurological disorders, or unstable systemic medical diseases that in the opinion of the investigator are likely to affect the central nervous system.
• Pregnant and/or breastfeeding.
• Received investigational agents as part of a separate study within 30 days of the screening visit.
• Actively suicidal/presence of suicidal ideation or evaluated as being at suicide risk (as per clinical judgment).
• Currently receiving treatment with Monoamine Oxidase Inhibitors (MAOIs) antidepressants, antibiotics such as linezolid, or intravenous methylene blue.
• Previous hypersensitivity reaction to vortioxetine or any components of the formulation. Angioedema has been reported in patients treated with vortioxetine.
• Serotonin syndrome.
• Abnormal bleeding.
• Previous history of mania/hypomania.
• Angle closure glaucoma.
• Hyponatremia.
• Moderate hepatic impairment.
• Active seizure disorder/epilepsy, not controlled by medication
• Presence of any unstable medical conditions.

Adverse events will be collected from baseline (Week 1) to endpoint (Week 8).

participants not stratified as part of eligibility on the basis of having a predetermined threshold of objective cognitive impairment prior to enrolment. Participants in our study were primarily recruited via media announcements including presentations at Post COVID-19 Condition online groups. Our sample was not recruited from a medical clinic including "Post COVID-19 Condition clinics." Majority of participants were Caucasian; it is recognized that our results may not generalizable.